Thiosubstituted pyridines

ABSTRACT

3-Trifluoromethylthio-2-(3-loweralkylamino-2-R 1  O-propoxy)pyridines, their pharmaceutically acceptable salts certain intermediates and their preparation are disclosed. These pyridines have pharmaceutical properties such as antihypertensive activity of rapid onset.

BACKGROUND OF THE INVENTION

The present invention concerns 3-CF₃ S-2-(3-lower-alkylamino-2-R₁O-propoxy)pyridines having pharmaceutically useful properties, certainintermediates and their preparation.

Hypertension in man and other animals can be treated with variouschemical agents. One such class of agents is that known as theβ-adrenergic blocking agents or β-blockers. While this class of agentscan have antihypertensive activity, the onset of this activity isgenerally gradual. The structure and activity of β-blockers is generallydiscussed in "Clinical Pharmacology and Therapeutics" 10, 252, 306(1969). Substituted N-heteroaryl β-adrenergic blocking agents aredisclosed in U.S. Pat. No. 4,000,282, U.S. 4,060,601, German applicationNo. 2,406,930, its counterpart South African patent No. 74 28204,British Pat. No. 1,305,644, Journal of Medicinal Chemistry 16, 1113-1114(1973) and Journal of Medicinal Chemistry 15, 1321 (1972).

Novel 3-CF₃ S-2-(3-loweralkylamino-2-R₁ O-propoxy)pyridines have beendiscovered. These compounds have antihypertensive activity of rapidonset and are β-adrenergic blocking agents.

SUMMARY OF THE INVENTION

3-CF₃ S-2-(3-loweralkylamino-2-R₁ O-propoxy)-pyridines theirpharmaceutical use, certain intermediates and their preparation.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

An embodiment of the present invention is compounds having the formula##STR1## wherein R is C₁ -C₆ alkyl, preferably C₃ -C₄ branched alkyl and

R₁ is H or ##STR2## wherein L is C₁ C₁₀ alkyl, phenyl and substitutedphenyl having up to two substituents which are independently selectedfrom C₁ -C₄ alkoxy, halo and C₁ C₄ alkyl

and pharmacuetically acceptable salts thereof.

The L group includes C₁ -C₁₀, linear and branched, hydrocarbon alkylsuch as methyl, n-decyl, tert. butyl, isoamyl, n-heptyl and the likewith C₁ -C₄ alkyl being preferred, and mono- and di-substituted phenylsuch as 4-tert. butylphenyl, 2,6-dibromophenyl, 3-methylphenyl,4-n-propylphenyl, 3,5-dimethoxyphenyl, 4-iodophenyl,2-methyl-4-chlorophenyl, 4-fluorophenyl and the like, withmono-substituted phenyl preferred. Compounds where R₁ is H are mostpreferred.

R is isopropyl, sec. butyl,CH₃,tert. butyl, C₆ H₁₁, with tert. butylbeing most preferred.

Examples of useful Formula I compounds are ##STR3## and the like.

Preferred compounds of formula I are those where R is isopropyl or tertbutyl. More preferred compounds are those where R₁ is H.

The especially preferred compounds are those wherein R is isopropyl ort-butyl and R₁ is H; and the most preferred compound has the formula##STR4##

The Formula I pyridines of the present invention include all the opticalisomer forms, that is mixtures of enantiomers e.g. racemates as well asthe individual enantiomers. These individual enantiomers are commonlydesignated according to the optical rotation they effect, by (+) and(-), (L) and (D), (1) and (d) or combinations of these symbols. Thesymbols (S) and (R) stand for sinister and rectus respectively anddesignate an absolute spatial configuration of the enantiomer. The (S)isomer form is the more preferred form.

The pyridines of the present invention can be prepared by any convenientprocess.

One such process involves the coupling of a halopyridine with a suitablesubstituted oxazolidine and hydrolysing the reaction product obtained.The process yields Formula I compounds where R₁ is H and is illustratedby the following set of reaction equations: ##STR5## Halo may be Cl orBr, with Br being preferred. M is an alkali metal, either potassium orsodium. Y can be hydrogen or the residue of any suitable aldehyde##STR6## e.g. an arylaldehyde, such as benzaldehyde, naphthaldehyde andthe like, or an alkanal such as acetaldehyde, butyraldehyde and thelike. The process for preparing oxazolidines where M is hydrogen isdisclosed in U.S. Pat. No. 3,718,647, U.S. Pat. No. 4,000,282, U.S. Pat.No. 3,657,237 and U.S. Pat. No. 4,060,601 and to the extent necessarythe pertinent disclosure is incorporated herein by reference. The alkalimetal salt of the oxazolidine is prepared in a conventional manner byreaction of the corresponding hydroxymethyloxazolidine with anappropriate amount of an alkali base reactant. However, this Reaction Amay also be carried out with in-situ formation of the alkali metaloxazolidine salt (Formula IV) by reacting the oxazolidine ##STR7## withthe Formula III pyridine in the presence of a strong base which as analkali metal alkoxide (e.g. K--O--C--(CH₃)₃) or sodium hydride.

The coupling reaction can be carried out at temperatures ranging fromabout 0° to about 100° C. A temperature range of about 10° to about 50°C. is preferred. The reaction is generally carried out in a solvent. Anysuitable solvent may be used. Examples of useful solvents aredimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, tert.butanol, alkanols and the like. The hydrolysis is carried out usingconventional acid hydrolysis reagent and techniques e.g. treatment witha solution of any strong mineral acid such as HCl or H₂ SO₄. Thehydrolysis product can be directly obtained as the salt of the acid usedfor the hydrolysis. Ordinarily, the product Ia is recovered as the freebase after conventional neutralization of the salt.

The coupling reaction is ordinarily carried out at atmospheric pressure.Higher pressures may be used is desired.

When a racemic oxazolidine (Formula IV or VI) is used as a reactant, theproduct is obtained as a racemate. The racemate may be separated intoits individual enantiomers by conventional resolution techniques.

By using a single optical isomer of said oxazolidine in the abovereactions, the product may be obtained directly as a single enantiomer.Thus, if the S-isomer of the oxazolidine is used, then the productobtained will be the S-isomer. This provides a convenient way fordirectly preparing individual isomers of the present pyridines.

Pyridines of the present invention wherein R₁ is other than hydrogen areconveniently prepared by treating the corresponding pyridine where R₁ ishydrogen with an appropriate acylating agent such as an acyl halide,e.g. undecanoyl chloride, pivaloyl chloride, benzoylchloride,p-methoxybenzoyl chloride, an anhydride e.g. acetic anhydride, and thelike. The reaction is illustrated by the following equations: ##STR8##

The compounds of the present invention also include the pharmaceuticallyacceptable salts of the novel pyridines. These salts are generally saltsof the Formula I pyridines and organic or inorganic acids. These saltsare prepared by treating the pyridine with an appropriate amount of auseful acid, generally in a suitable solvent. Examples of useful organicacids are carboxylic acids such as maleic acid, acetic acid, tartaricacid, propionic acid, fumaric acid, isethionic acid, succinic acid,pamoic acid, oxalic acid, pivalic acid and the like; useful inorganicacids are hydrohalo acids such as HCl, HBr, HI; sulfuric acid,phosphoric acid and the like. The hydrochloride and hydrogen maleatesalts are examples of preferred salts.

The compounds of the present invention have antihypertensive activity ofrapid onset and are also β-adrenergic blocking agents. One advantage thepresent pyridines have over ordinary β-adrenergic blocking agents isthat the antihypertensive effect is immediate and generally of extendedduration.

This rapid onset antihypertensive activity is determined byadministering (orally) a representative pyridine of the presentinvention to spontaneously hypertensive (SH) rats and measuring theeffect on blood pressure. An example of a representative compound havingthis antihypertensive activity is (S)-2-(3-tert.butylamino-2-hydroxypropoxy)-3-trifluoromethylthiopyridine.

The β-adrenergic blocking activity of the Formula I pyridines isdetermined by measuring the ability of a representative pyridine toblock isoproterenol induced β-adrenergic stimulant effects such as heartrate increase, hypotension and bronchodilation, in animals.

The ability of the Formula I pyridines to reduce blood pressure, in anSH rat, rapidly and for extended duration, indicates that the presentpyridines and their salts are useful to treat hypertension in humans.Likewise, the observed β-adrenergic blocking activity of these pyridinesindicates that they are useful in humans as β-adrenergic blockingagents.

For use as antihypertensives and/or β-adrenergic blocking agents, thecompounds of the present invention can be administered orally, byinhalation, by suppository or parenterally i.e. intravenously,intraperitoneally, etc. and in any suitable dosage form. The compoundsmay be offered in a form (1) for oral administration e.g. as tablets incombination with other compounding ingredients (diluents or carriers)customarily used such as talc, vegetable oils, polyols, benzyl alcohols,starches gelatin and the like--or dissolved, dispersed or emulsified ina suitable liquid carrier--or in capsules or encapsulated in a suitableencapsulating material; or (2) for parenteral administration, dissolved,dispersed, or emulsified in a suitable liquid carrier or diluent or (3)as an aerosol or (4) as a suppository. The ratio of active ingredient(Formula I pyridine) to compounding ingredients will vary as the dosageform requires. Concentional procedures are used to prepare thepharmaceutical formulations.

The dosage level for the present compounds may be varied from about 0.01mg. to about 50 mg. per kilogram of animal body weight per day. Dailydoses ranging from about 0.04 to about 2.5 mg/kg are preferred, withabout 0.08 to about 1.35 mg/kg being a more preferred range. Oraladministration is preferred. Either single or multiple daily doses maybe administered depending on unit dosage.

Thus, another embodiment of this invention is a pharmaceuticalcomposition containing an antihypertensive and/or β-adrenergic blockingamount of a Formula I compound of the present invention.

Other embodiments of the present invention are the halopyridineintermediates of Formula III namely ##STR9## and the method of theirpreparation according to the process illustrated by the following set ofreactions. ##STR10## Condensation agent may be an organic acid anhydridee.g. acetic anhydride and the catalyst is preferably a metallic halidesuch as ZnCl₂. The cyclization is effected in a suitable system such asH Br and acetic acid.

The following examples illustrate the preparation of (1) a formula IIIintermediate using the Sequence B process and (3) a representativecompound of Formula I. All temperatures are in degrees Celsius.

EXAMPLE I Preparation of 2-bromo-3-trifluoromethylthiopyridine

A solution of acetic anhydride (52 mL), 1,1,3,3-tetramethoxypropane(26.4 g, 0.16 mL), trifluoromethylthioacetonitrile (14.5 g, 0.1 mol) andZnCl₂ (1 g) was heated at reflux. After 18 hours, the mixture wasdistilled up to 100° at atmospheric pressure. The residue was thencooled to 25° C. and filtered. The clear solution was distilled to yield3.5 g of 4-cyano-4-trifluoromethylthio-3-butenealdehydedimethylacetal(bp 65°-93° C. at 18 mm) and 5.3 g of1-cyano-1-trifluoromethylthio-4-methoxy-1,3-butadiene (bp 83°-105° C. at0.5 mm). This material was combined and used in the next step withoutfurther purification.

A solution of 30% HBr, AcOH (70 mL) was added dropwise with stirring at40° C. to a solution of4-cyano-4-trifluoromethylthio-3-butenealdehydedimethylacetal and1-cyano-1-trifluoromethylthio-4-methoxy-1,3-butadiene (8.8 g) in AcOH(40 mL). After the addition, the solution was heated at 55° C. for 2hours, poured onto ice and neutralized with solid Na₂ CO₃. The solutionwas extracted with CH₂ Cl₂ (3x) and the CH₂ Cl₂ extracts dried, filteredand concentrated to dryness. The residual oil was distilled at 68°-71°C. at 0.3 mm of yield 4.0 g (16%) of2-bromo-3-trifluoromethylthiopyridine ¹ H NMR (CDCL₃) δ7.35 (1H, dd, J=4and 8), 8.05 (1H, dd, J=2 and 8), 8.45 (1H, dd, J=3 and 4); ¹⁹ F NFR(CDCl₃)+40.7 (s).

The exact mass was 256.9130 (calcd for C₆ H₃ NBr⁷⁹ SF₃, 256.9122) and258.9130 (calcd for C₆ H₃ NBr⁸¹ SF₃, 258.8102).

EXAMPLE 2 (S)2-(3-tert-butylamino-2-hydroxypropoxy)-3-trifluoromethylthiopyridinemaleate salt

Into a flame dried flask under N₂ is placed tert-butanol (200 ml),potassium metal (0.7 g, 0.018 mol) and (S)2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine (5.0 g, 0.02 mol) andthe mixture heated at 40° C. with stirring. After the potassium metalhad reacted, a solution of 2-bromo-3-trifluoromethylthiopyridine (4.0 g,0.015 mol) in tert-butanol (100 ml) was added dropwise. After theaddition, the solution was heated at 70°-80° C. for 15 hours. Thetert-butanol was removed under reduced pressure, H₂ O added to theresidue and the pH of the resulting solution adjusted to pH 2-3 with 3 NHCl. After stirring for 45 minutes at 25° C., the aqueous layer wasextracted with Et₂ O (2x), poured into saturated Na₂ CO₃ solution andextracted with CHCl₃ (3x). The CHCl₃ layer was dried over Na₂ SO₄,filtered and concentrated to dryness. The residue was chromotographed onsilica gel and the product eluted with 20% CH₃ OH-CHCl₃ to yield 1.4 g(29%) of the free base2-(3-tert-butylamino-2-hydroxypropoxy)-3-trifluoromethylthiopyridine).The residue was crystallized as the maleate salt from EtOH-Et₂ O toyield 0.8 g of (S)2-(3-tert-butylamino-2-hydroxypropoxy)-3-trifluoromethylthiopyridinemaleate salt m.p. 108°-100° C.

What is claimed is:
 1. A compound having the formula ##STR11## andpharmaceutically acceptable salts thereof wherein R is H or C₁ -C₆ alkyland R¹ is H or ##STR12## wherein L is C₁ -C₁₀ alkyl, phenyl orsubstituted phenyl having up to two substituents independently selectedfrom C₁ -C₄ alkoxy, halo and C₁ -C₄ alkyl.
 2. A compound of claim 1wherein R is C₃ -C₄ branched alkyl.
 3. A compound of claim 1 wherein R¹is H.
 4. A compound of claim 3 wherein R is isopropyl or t-butyl.
 5. Acompound of claim 4 wherein R is isopropyl.
 6. A compound of claim 4wherein R is t-butyl.
 7. The S-isomer of the compound of claim
 1. 8. Apharmaceutical composition for treating hypertension containing aneffective amount of the compound of claim 1 and a carrier.